Hypertension is a major public health concern in the U.S. and affects ~70 million adults. Up to 36% of military Veterans have hypertension which is the primary risk-factor for development of stroke and other cardio- vascular diseases. Poor nutrition is a risk factor for heart disease and stroke. Fructose intake has increased in the general population and also in Veterans with up to 25% of Veterans consuming more than 82 g of fructose per person per day compared with only 0.8 g per person per day in 1970, a 100-fold increase. High fructose intake exceeds the ability of the liver to convert fructose to glucose, so that fructose enters the bloodstream which normally does not occur. Fructose ingestion in and of itself has been linked to hypertension by a variety of mechanisms. Circulating fructose (a) enhances sodium absorption by the gut and decreases renal sodium excretion, leading to plasma volume expansion, (b) activates the renin-angiotensin system and upregulates brain angiotensin (Ang II) receptors (AT1R), and (c) can be transported across the blood brain barrier and is concentrated up to 30-fold in cerebrospinal fluid where it can contribute to sympathetic overdrive. Plasma volume expansion together with Ang II and sympathetic over activity can then result in increased arterial pressure. Brain AT1R are upregulated in fructose-fed rats. The subfornical organ (SFO) which is outside the blood brain barrier is well endowed with AT1R and projects to the paraventricular nucleus (PVN) which influences sympathetic tone. Fructose has the potential to enhance sympathetic responses by influencing the neuronal sodium potassium chloride co-transporter (NKCC1) or the potassium chloride co-transporter (KCC2) within the PVN, similar to actions of fructose on renal transporters. These transporters impart functional plasticity to GABAergic neurons and limit GABA inhibition of sympathetic outputs, further contributing to neuroexcitability. Sympathetic input to the kidney stimulates renin secretion and subsequent Ang II generation, resulting in a vicious cycle. Existing evidence has been indirect with prolonged and/or high exposure to fructose and cannot distinguish whether fructose ingestion itself results in high Ang II, sympathoexcitation and hypertension or whether the elevated Ang II and sympathoexcitation are a consequence of the metabolic syndrome. In this proposal we will test the hypothesis that a high fructose intake combined with a high sodium chloride diet in rats results in elevated blood pressure due to activation of the renin-angiotensin system and enhanced RSNA prior to development of the metabolic syndrome that can be mitigated by regular exercise. Three specific aims will be addressed: (1) fructose-fed, but not glucose-fed, rats on a high NaCl diet will have higher basal arterial pressure, plasma renin activity (PRA), angiotensin II (Ang II) levels and RSNA within 7 to 28 days as well as greater responses to acute stress; (2) arterial pressure, heart rate and RSNA will be augmented in fructose-fed rats on high NaCl diet but not in glucose-fed rats on the same NaCl diet due to fructose-induced functional plasticity in PVN-GABAergic modulation of sympathetic outputs; and (3) elevated arterial pressure, PRA, Ang II and RSNA as well as stress responses in fructose-fed rats on high NaCl diet will be decreased by a program of daily voluntary wheel running exercise due to restoration of GABAergic inhibition of sympathetic output. These studies will provide substantive evidence for initiatives to address nutritional recommendations and exercise regimens even in lean, non-diabetic individuals to treat and even prevent hypertension and its consequences. In addition, novel chloride extrusion enhancers or blockers of chloride entry that increase GABAergic inhibition signaling are being tested as treatments for pain and other neurological diseases and may also have potential to exploit the plasticity of central sympathoinhibitory pathways to mitigate the risk of stroke and disability. Exercise be too risky for patients with uncontrolled hypertension or difficult for disabled individuals who have sustained a stroke. The ability to mimic the beneficial effects of exercise by modifying chloride potential will be of substantial clinical benefit to our Veterans.